Safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies.

PURPOSE: Immune checkpoint inhibitors (ICIs) show promising clinical activity in advanced cancers. However, the safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies (ANA) are unclear. METHODS: 191 patients treated with nivolumab, pembrolizumab, atezolizumab, or durvalumab for unresectable advanced cancers between September 2014 and December 2018 were identified retrospectively. Patients were divided into positive (ANA titers ≥ 1:160) and negative ANA groups (ANA titers < 1:160). Development of immune-related adverse events (irAEs), the overall response rate (ORR), and disease control rate (DCR) were monitored. RESULTS: Positive ANA titers were seen in 9 out of 191 patients. Four patients in the positive ANA group and 69 patients in the negative group developed irAEs of any grade without a significant difference between the groups. The development of endocrine, pulmonary, and cutaneous irAEs was not significant, whereas positive ANA was significantly higher in patients who developed colitis (2/9) than in patients who did not (3/182, P = 0.0002). DCR in the positive and negative ANA group was 37.5% and 67.5%, respectively, and was not statistically significant, but had better efficacy in patients without ANA (P = 0.08). ANA-related autoimmune diseases such as SLE, Sjögren's syndrome, MCTD, scleroderma, dermatomyositis, and polymyositis was not induced in either group. However, one patient with preexisting dermatomyositis had a flare up after initiation of atezolizumab. CONCLUSION: Further studies to identify predictive factors for the development of irAEs are required to provide relevant patient care and maximize the therapeutic benefits of ICIs.

Tetracycline-inducible promoter-based conditionally replicative adenoviruses for the control of viral replication.

The use of conditionally replicative adenoviruses (CRAds) as a promising strategy for cancer gene therapy has been developed to overcome inefficient transduction of solid tumor masses by replication-deficient adenoviruses. Many modifications have been made to CRAds to enlarge tropism, increase selectivity and lytic ability, and improve safety. However, safety is still a concern in the context of future clinical application of CRAds. Particularly, after injection into the body, viral replication cannot be controlled externally. Therefore, we constructed a novel CRAd using a tetracycline-inducible promoter system to realize external pharmacological control of its replication. The effect of this CRAd in vitro was measured at the levels of viral DNA replication, cell death and progeny production. We showed that CRAd replication was tightly controlled by the presence or absence of doxycycline (Dox). Moreover, this system showed a significant gene expression in vivo, in which the viral replication was controlled by the oral administration of Dox. This strategy may help improve the safety of cancer gene therapy.

Tumor targeting carboxylesterase fused with anti-CEA scFv improve the anticancer effect with a less toxic dose of irinotecan.

Irinotecan (CPT-11) is a key drug for the treatment of various cancers. CPT-11 can be considered to be a prodrug, since it needs to be activated into the toxic drug SN-38 by the enzyme carboxylesterase. However, CPT-11 may induce severe diarrhea and bone marrow suppression as adverse effects, thus leading to treatment interruption. The tumor-specific activation of CPT-11 is a possible strategy to avoid the severe toxicities by reducing the serum concentration of CPT-11. In this study, we constructed human liver carboxylesterase-2 fused with anticarcinoembryonic antigen (CEA) scFv as a targeting molecule. The recombinant enzyme anchors onto the tumor cell surface CEA, and thus metabolize CPT-11 extracellularly. In addition a secreted tumor-targeted form of carboxylesterase should help prevent the leakage of the enzyme from the site of the tumor into the circulation. This fusion protein showed CPT-11 activation to SN-38 and specific binding to CEA-expressing cells. In combination with CPT-11, the recombinant carboxylesterase protein exerted antiproliferative effects on human cancer cells. This recombinant enzyme is, therefore, a promising new tool in enzyme prodrug therapy for the treatment of carcinoma with CPT-11.

Vascular endothelial growth factor promoter-based conditionally replicative adenoviruses for pan-carcinoma application.

Treatment of advanced lung cancer is one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and has an extremely poor prognosis. Thus, new therapeutic approaches are needed. Lung tumor formation depends on angiogenesis in which the vascular endothelial growth factor (VEGF) produced by cancer cells plays a pivotal role. Neutralizing VEGF with a soluble VEGF receptor suppresses tumor growth; however, the anticancer effect with this therapy is weakened after the intratumoral vascular network is completed. In this study, we turned the expression of VEGF by tumors to therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 is controlled by the human VEGF promoter. This virus achieved good levels of viral replication in lung cancer cells and induced a substantial anticancer effect in vitro and in vivo. As a further enhancement, the cancer cell killing effect was improved with tropism modification of the virus to express the knob domain of Ad3, which improved infectivity for cancer cells. These VEGF promoter-based CRAds also showed a significant cell killing effect for various types of cancer lines other than lung cancer. Conversely, the VEGF promoter has low activity in normal tissues, and the CRAd caused no damage to normal bronchial epithelial cells. Since tumor-associated angiogenesis via VEGF signalling is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that VEGF promoter-based CRAds have the potential to be an effective strategy for cancer treatment.

Prevention of radiation-induced pneumonitis by recombinant adenovirus-mediated transferring of soluble TGF-beta type II receptor gene.

To investigate whether radiation-induced pneumonitis in the mouse-irradiated lung could be prevented by recombinant adenovirus-mediated soluble transforming growth factor-beta (TGF-beta) type II receptor gene therapy. Radiation fibrosis-prone mice (C57BL/6J) were randomly divided into four groups consisting of a (1) control group (sham-irradiated); (2) radiation (RT)-alone group; (3) RT+AdCMVsTbetaR group and (4) RT+AdCMVluc group. The RT-alone and sham-irradiated mice were killed at several time points after thoracic irradiation with a single dose of 9 Gy, and then the TGF-beta1 concentrations in serum and broncho-alveolar lavage fluid (BALF) were quantified by enzyme-linked immunosorbent assay (ELISA). We used an adenoviral vector expressing a soluble TGF-beta type II receptor (AdCMVsTbetaR), which can bind to TGF-beta and then block the TGF-beta receptor-mediated signal transduction. The C57BL/6J mice were intraperitoneally (i.p.) injected with either 5 x 10(8) plaque-forming units of AdCMVsTbetaR or AdCMVluc, a control adenovirus-expressing luciferase, a week preceding and a week following the X-ray thoracic irradiation. Four weeks after irradiation, the mice were killed and the concentration of TGF-beta1 in the serum and BALF were then measured using ELISA and the lung tissue specimens were examined histopathologically. Following thoracic irradiation with a single dose of 9 Gy, radiation-induced TGF-beta1 release in the serum reached the first peak concentration at 12 h and then declined. It reached a maximal value at 2 weeks after irradiation. In the BALF, the TGF-beta1 concentration was appreciable within the first hour and thereafter declined. It reached a maximal value at 3 days after irradiation. A one-time i.p. injection of AdCMVsTbetaR 1 week before irradiation could not completely suppress the two peaks of the radiation-induced TGF-beta1 increase, whereas an injection a week preceding and a week following thoracic irradiation was able to suppress those two peaks thoroughly. The TGF-beta1 was completely suppressed in the AdCMVsTbetaR-treated mouse serum and BALF; however, no statistical difference was observed in the serum and BALF between the AdCMVluc-infected mice and the control mice at 4 weeks after irradiation (P < 0.05). A histopathological examination showed only mild radiation pneumonitis in the irradiated lungs of AdCMVsTbetaR-treated mice in comparison to the AdCMVluc-infected and RT-alone mice. Our results demonstrated that TGF-beta1 plays an important role in radiation pneumonitis, thus suggesting that the adenovirus-mediated overexpression in soluble TGF-beta type II receptor gene therapy may be a potentially feasible and effective strategy for the prevention of radiation pneumonitis.

Outcome of hepatoblastoma treated with the JPLT-1 (Japanese Study Group for Pediatric Liver Tumor) Protocol-1: A report from the Japanese Study Group for Pediatric Liver Tumor.

PURPOSE: Hepatoblastoma is the most common malignant liver tumor in childhood. Multicenter studies elucidate the optimal pre- or postoperative chemotherapeutic regimens. This report reviews the results of the Japanese Study Group for Pediatric Liver Tumor Protocol-1 (JPLT-1) and compares its outcomes with published reports of other studies. METHODS: From March 1991 to December 1999, 154 patients with malignant liver tumor including 145 cases of hepatoblastomas were enrolled in the JPLT study. Data from 134 cases were analyzed in this study. JPLT-1 protocol 91A was used for patients with stage I or II hepatoblastoma. The chemotherapy regimen consisted of repeated courses of cisplatin (CDDP), 40 mg/m(2), and tetrahydropyranyl (THP)-Adriamycin, 30 mg/m(2). JPLT-1 protocol 91B was administered to patients with stage IIIA, IIIB, or IV hepatoblastoma. The chemotherapy regimen consisted of repeated courses of CDDP, 80 mg/m(2), and THP-Adriamycin, 30 mg/m(2)/day for 2 days. Courses were repeated every 4 weeks as tolerated. RESULTS: Seven patients died of chemotherapy-related side effects. Six of them died of sepsis caused by leukopenia and 1 case of liver failure. Overall survival rate (3-year/6-year) was 100%/100% for stage I (n = 9), 100%/95.7% for stage II (n = 32), 76.6%/73.8% for stage IIIA (n = 48), 50.3%/50.3% for stage IIIB (n = 25), 64.8%/38.9% for stage IV (n = 20), and 77.8%/73.4% overall. For stage IIIA and B disease, intravenous chemotherapy was better than intraarterial chemotherapy (66.4% v 38.1% for event-free survival and 69.3% v. 57.1% for overall survival). Patients less than 1 year of age had a better prognosis than older patients, but age was not a significant prognostic factor by multivariate analysis. CONCLUSIONS: The overall and event-free survival rates of the JPLT-1 study of hepatoblastoma were comparable with the results of other multicenter studies in Europe and the United States. The event-free survival rate at 3 years for stage IIIB and IV disease was under 50%. New treatment strategies are needed for patients with advanced hepatoblastoma.

Development of language in Rett syndrome.

Ninety-nine cases of Rett syndrome (RTT) diagnosed clinically (age range 3 years 6 months to 29 years 9 months) were evaluated for the ability of language. The presence of meaningful words, vocabularies, and ages at the start and disappearance of speech were assessed. Phenotype/genotype correlation was evaluated in 22 cases in whom mutations of the genes of methyl-CpG-binding protein 2 (MECP2) existed. Fifty-five cases (55.5%) could speak some words, and of them eight cases (14.5%) spoke two-word sentences. No case had more than 40 words. The vocabularies were mainly bilabial words, known as the characteristics of the initial words in normal children. They began to utter a word between 12 and 48 months, and most of them (85.4%) before 20 months. Those who spoke two-word sentence(s) began to utter a word earlier (10.4+/-3.7 months) than others (17.1+/-9.8 months). Thirty-three cases lost their word(s) in 12-36 months. Among 22 gene-proven cases two cases with mutation of R133C and two cases with R294X had word(s), but another two cases with T158M had not. In RTT a delay in the neuronal systems involved in normal speech development was suggested and its severity seemed to depend on the loci of mutation.

Primary lung cancer occurring concomitantly with the cicatrized and calcified ova of a parasite: report of a case.

We report herein a rare case of primary lung cancer that occurred concomitantly with the calcified ova of a parasite. A 58-year-old man was referred to our department after a pulmonary abnormal shadow had been seen on a chest X-ray done at mass screening. A transbronchial lung biopsy (TBLB) revealed the calcified ova of a parasite. Because the possibility of concomitant lung cancer could not be ruled out, a lung biopsy was taken via video-assisted thoracic surgery (VATS). The pathological diagnosis was squamous cell carcinoma, and a left upper lobectomy was serially performed through a posterolateral thoracotomy. The patient recovered uneventfully and has remained in good health without any sign of recurrence for over 9 months. Following this case report, we review three other cases of this unusual disease combination documented in the literature.

Intratumoral pyrimidine nucleoside phosphorylase (PyNPase) activity predicts a selective effect of adjuvant 5'-deoxy-5-fluorouridine (5'DFUR) on breast cancer.

BACKGROUND: Pyrimidine nucleoside phosphorylase (PyNPase) is the enzyme that converts 5'-deoxy-5-fluorouracil (5'DFUR) to 5-fluorouracil (5FU). Its activity in cancer tissue may correlate with the selective antitumor activity of 5'DFUR in breast cancer. METHODS: Two hundred and sixteen T2 breast cancer patients were treated consecutively with surgery followed by 5'DFUR (600 mg/body/day) + tamoxifen (20 mg/body/day) for 2 years. PyNPase activity in breast cancer tissue, determined by high-performance liquid chromatography, ranged from 4.2-626.0 micrograms FU/mg protein/hr (mean +/- SD, 203.5 +/- 122.4), and the examined patients were divided into two groups: group A (high PyNPase group), cases with the PyNPase activity equal to or more than the mean value of 203.5 micrograms FU/mg protein/hr, and group B (low PyNPase group), cases with activity less than the mean value. RESULTS: Although there was no difference in relapse-free survival (RFS) between groups A and B, among node-positive patients (n = 83) those in group A tended to have a longer RFS. When divided into subgroups according to estrogen receptor (ER) status, among node-positive and ER-positive tumors (n = 49), the RFS was significantly better in group A than in group B (p < 0.05). CONCLUSION: Intratumoral PyNPase activity might be of use as a predictor of the effect of adjuvant 5'DFUR on breast cancer.

UFT and mitomycin plus tamoxifen for stage II, ER-positive breast cancer. Hokkaido ACETBC Study Group.

A trial was designed to examine the combination of UFT and mitomycin (Mutamycin) plus tamoxifen (Nolvadex) as postoperative adjuvant therapy in the treatment of patients with stage II, estrogen receptor (ER)-positive primary breast cancer. Mitomycin was administered intravenously at 13 mg/m2 on the day of surgery. Patients judged to be ER-positive were randomly allocated to either group A, which received oral tamoxifen 20 mg/day 14 days after surgery for 2 years, or group B, receiving oral UFT 400 mg/day plus tamoxifen 20 mg/day. A total of 219 patients were enrolled in group A, of which 213 (97.3%) were determined to be eligible; 225 patients enrolled in group B and 223 (99.1%) were eligible. The 5-year survival rates were 93.0% for group A and 95.4% for group B, with no significant difference between groups. The 5-year relapse-free survival rates were 83.1% for group A and 90.7% for group B, a significant advantage (P = .020) for the UFT plus tamoxifen group. Combination therapy with mitomycin, tamoxifen, and UFT proved to be an effective postoperative chemoendocrine therapy for stage II, ER-positive breast cancer.

Treatment results of advanced neuroblastoma with the first Japanese study group protocol. Study Group of Japan for Treatment of Advanced Neuroblastoma.

PURPOSE: To elucidate the efficacy of intensive induction and consolidation chemotherapy regimens (Study Group of Japan for Advanced Neuroblastoma [JANB] 85) for patients with advanced neuroblastoma aged 1 year or older. PATIENT AND METHODS: One hundred fifty-seven patients with newly diagnosed advanced neuroblastoma were entered into this study between January 1985 and December 1990. Eligible patients were 12 months old or older with stage III or IV disease. The patients first received six cyclic courses of intensive induction chemotherapy (designated regimen A1) consisting of cyclophosphamide (1,200 mg/m2), vincristine (1.5 mg/m2), tetrahydro-pyranyl Adriamycin (pirarubicin; 40 mg/m2), and cisplatin (90 mg/m2). The patients were further treated with three different consolidation protocols: 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosour ea, dacarbazine, and bone marrow transplantation. RESULTS: Overall survival rates for patients with stage III disease without reference to the consolidation protocols were 80.8%, 76.9%, and 66.3% at 2, 5, and 10 years, respectively. The overall survival rates for patients with stage IV disease were 58.8%, 34.4%, and 28.9% at 2, 5, and 10 years, respectively. There were no statistically significant differences between the three consolidation treatment groups. Patients who did not achieve complete remission (CR) with induction chemotherapy and surgery all died, suggesting that CR is essential for the cure of advanced neuroblastoma. The overall 5-year survival rate of the 24 patients with N-myc amplified stage III and IV disease was 33.3%, and the longest survival time of a relapse-free patient was 103 months. CONCLUSION: The intensive induction chemotherapy regimen used in this study may be of significant value in increasing the CR rate and survival for patients with N-myc amplified and nonamplified advanced neuroblastoma.

[Comparison of crossing-over between 30-minute drip infusion vs 30-second injection of granisetron for nausea and vomitting with cisplatin].

Recently, Granisetron (KYT) was proved to have a strong effect for cisplatin (CDDP)-induced emesis. We compared the effect of KYT for CDDP-induced emesis between two different administration schedules. Forty micrograms/kg of KYT was administered either by 30-minute drip infusion with 100 ml of saline (Group A) or 30-second injection with 10 ml of saline (Group B). We investigated the therapeutic effect of KYT in both group A and Group B by the crossing-over method. After the patients who had a malignant tumor and were going to receive CDDP (over 50 mg/m2) in two courses were selected, KYT was administered by the method of Group A or Group B in a double-blind comparison. The clinical efficacy was at least "effective" in 70% (7/10) of Group A and Group B. The study treatment was considered "useful" in 80% (8/10) of Group A, 90% (9/10) of Group B, and "safe" in 100% of Group A and B. There was no difference between two groups in this respect. The results showed that the slow intravenous injection of KYT also has an excellent antiemetic effect on CDDP-induced emesis and a high degree of safety.

Laparoscopic cholecystectomy: a report on the community hospital experience in Hokkaido.

We analyzed the outcome of 1408 patients who underwent laparoscopic cholecystectomy (LC) between February 1991 and October 1993 in affiliated community hospitals around Hokkaido, Japan. LC was performed for symptomatic gallstones (68%) and asymptomatic gallstones (29%) using the pneumoperitoneum (96%) or abdominal wall lift (4%) techniques. Intraoperative and postoperative complications occurred in 105 patients (10%), including bile duct injuries in 9 patients (0.9%). Conversion to open surgery or reoperation was required in 89 patients (8%) mainly because of unclear anatomy, difficulties with hemostasis, or bile duct injury. One patient died of congestive heart failure, resulting in a mortality rate of 0.07%. The patients were discharged after an average of 8 days, and returned to work after an average of 14 days. The complication and conversion rates were high; however, the incidences of reoperation, bile duct injuries, postoperative bile leaks, and deaths were low. In conclusion, LC was performed with acceptable safety in our community hospitals. The reason for this is most likely that conventional cholecystectomy was preferred to LC in difficult cases during this early period.

Cyclophosphamide, adriamycin, 5-fluorouracil and high-dose toremifene for patients with advanced/recurrent breast cancer. The Japan Toremifene Cooperative Study Group.

BACKGROUND: Multi-combination chemotherapy consisting of anthracyclines has been effective but has not invariably prolonged the survival period in advanced/recurrent breast cancer. The possibility has been discussed that chemoendocrine therapy combined with endocrine agents is more effective. METHODS: In order to evaluate the toxicity and efficacy of a new endocrine therapy for advanced/recurrent breast cancer, we ran a pilot study during the period from July 1994 to July 1996. RESULTS: Twenty-two patients with advanced/recurrent breast cancer were treated with chemoendocrine therapy consisting of cyclophosphamide (100 mg/body) p.o. daily for 14 days, with adriamycin (40 mg/m2) i.v. and 5-fluorouracil (500 mg/body) i.v. on day 1 (repeated every 3 weeks for 9 weeks) (CAF therapy), and high-dose toremifene (120 mg/body) p.o. daily. Of 20 evaluable patients, two showed complete response (10%), eight partial response (40%), six no change (30%) and four progressive disease (20%). The overall response rate was 50%, and the median duration of response was 69.5 days (28-133+ days). The major toxicities were drug-induced alopecia, gastrointestinal toxicity and hematological toxicity, but these were clinically well tolerated. No serious cardiac, liver or renal symptom was seen. CONCLUSIONS: Based on these results, we consider the addition of high-dose toremifene to the CAF therapy to be useful in the treatment of advanced and recurrent breast cancer.

Transverse colonic stenosis.

A 3-year child presented with episodic lower abdominal pain; during the eighth attack, a mass was palpable in the left upper quadrant, and a barium enema revealed a stenotic area in the transverse colon. This was resected and an uneventful postoperative course followed. Subsequently, the child has remained symptom-free. instruments are no longer in use.

Hepatocyte growth factor enhances the invasion activity of human hepatocellular carcinoma cell lines.

We investigated whether hepatocyte growth factor (HGF) enhances the invasion activity of three human HCC cell lines, HLF, HLE, and HC-4, in vitro. The analysis of the invasiveness consisted of the production of u-PA and the chemotaxis for fibronectin. Invasion activity of all cell lines was enhanced by the addition of recombinant human hepatocyte growth factor (rhHGF) to the medium. HGF stimulated the production of u-PA in HLF cells. HGF accelerated the chemotaxis of HC-4 and HLE. These data suggest that HGF increase the invasion activity of human HCC cell lines by affecting the production of u-PA or the chemotaxis for fibronectin.

[Phase I study of TAT-59 (a new antiestrogen) in breast cancer. TAT-59 Study Group].

Phase I study of TAT-59 (Miproxifen), an antiestrogen developed in Japan for breast cancer, was conducted with the collaboration of 12 hospitals. A single dose of 1.25, 5, 10, 20, 40 and 80 mg, or 5 consecutive daily doses of 1.25, 5, 10, 20 and 40 mg/day, were given orally. After single dosing, no clinical adverse effects were found. Decrease of serum Na, Cl, Ca level and increase of serum LDH level were observed in one patient after a single dose of 5 mg of TAT. An increase in the serum LDH level was also observed in one patient after a single dose in the of 10 mg of TAT. An increase in the serum LDH level and total bilirubin, increase of eosinophil, K and milky serum were also observed in one patient after a single dose of 40 mg of TAT, respectively. All of these abnormal values returned to the normal level within 26 days after final administration of TAT. No adverse clinical findings nor abnormal laboratory findings were observed after consecutive administration of TAT. After postprandial single dosing, the time to reach the maximum serum concentration (Tmax) of DP-TAT, dephosphorylated metabolite of TAT, and its demethylated metabolite, DMDP, ranged from 5.0 to 7.3 hr and from 17.0 to 42.8 hr, respectively. The maximum serum concentration (Cmax) and AUC of DP and DMDP elevated in a dose-dependent manner. T1/2 of DP and DMDP ranged from 24.2 to 41.5, and from 91.9 to 214.7 hr, respectively. There were no significant differences between pharmacokinetics of TAT before and after food intake. Based on the above results, we concluded that a Phase II study should be conducted to evaluate the efficacy, safety and optimal dose of TAT.

Intraperitoneal dissemination probably caused by needle biopsy of alveolar echinococcosis of the liver: experimental study.

Alveolar echinococcosis of the liver (AEL) is a parasitosis with a potential for malignant tumor-like behavior. The disease is diagnosed by a combination of serologic tests, diagnostic images, and the histology of needle biopsy specimens. It remains unresolved whether the biopsy induces subsequent troubles. We designed this study to investigate critical problems after needle biopsy of AEL lesions using an experimental model. Five samples were prepared from the resected lesions of AEL patients: (A) 10% suspension of trypsin digests of the minced lesion; (B) 10% suspension of mesh-filtered sediment of the minced lesion; (C) 10% sediment suspension after washing the nonminced lesion; (D) supernatant after centrifuging intracystic fluid; (E) 10% sediment suspension after centrifuging intracystic fluid. A 1-ml aliquot of each sample was injected intraperitoneally into jirds (gerbils) or cotton rats, respectively. The animals were sacrificed 12 weeks later, and intraperitoneal metacestodes were observed. All samples except D developed metacestodes, and their histologies were all lesions of typical alveolar echinococcosis. These results suggest that a needle biopsy may cause intraperitoneal dissemination or tracial implantation of the parasites along the track of the needle.

Meta-Analysis of the Second Collaborative Study of Adjuvant Chemoendocrine Therapy for Breast Cancer (ACETBC) in Patients with Stage II, Estrogen-Receptor-Positive Breast Cancer.

The second 5-year study of postoperative adjuvant therapy in patients with breast cancer between 1985 and 1988 was performed by the Study Group for Adjuvant Chemoendocrine Therapy for Breast Canecr (ACETBC). This report describes the results of a meta-analysis of the outcome. A total of 3012 patients with stage II, estrogen-receptor-positive primary breast cancer who underwent radical surgery (total mastectomy with at least axillary dissection) were eligible for the analyses. On the day of surgery, all patients received 13 mg/m(2) of mitomycin C (MMC) intravenously. Patients were then given one of two adjuvant chemoendocrine therapies for 2 years:regimen A, consisting of tamoxifen citrate (TAM) 30 mg/day, or regimen B, consisting of TAM 30 mg/day plus tegafur (Futraful, FT)600 mg/day. The results from all eligible patients were included in a meta-analysis according to the method of Peto et al. The odds reduction rate was 12 +/-13% (log-rank test, P= 0.35)for the 5-year survival rate and 16 +/- 10% (log-rank test, P=0.093)for the 5-year non-recurrence rate. In terms of the 5-year non-recurrence rate. regimen B(with FT)yielded slightly, but not significantly, better results than regimen A. In addition, stratified analyses were carried out with respect to the 5-year non-recurrence rate. Regimen B(with FT)yielded significantly better results than regimen A in patients with four or more positive axillary nodes (log-rank test, P= 0.039) and yielded slightly, but not significantly, better results than regimen A in premenopausal patients (log-rank test, P= 0.079).

Efficacy of Post-operative Adjuvant Therapy for Stage IIIa Berast Cancer: Futraful vs Futraful+Tamoxifen for ER-positive Patients and Futraful vs Futraful+Adriamycin for ER-negative Breast Cancer.

A multi-center, randomized controlled collaborative study was conducted in 310 institutions located thruoughout Japan for 3 years and 9 months from February 1985 until October 1988 to evaluate the efficacy of post-operative adjuvant therapy for patients who had previously undergone curative surgery for treatment of Stage III a breast cancer. Patients with estrogen receptor-positive [ ER(+)] breast cancer were treated with two types of regimens, ie, cyclophosphamide+adriamycin+fluorouracil (CAF; 2 cycles) +Futraful(FT) or CAF (2 cycles+FT+tamoxifen (TAM), and the clinical benefit of additional use of TAM was evaluated. Of the 509 ER(+) patients registered for the trial, 473 patients (92.9%) were eligible for evaluation.The 5-year survival rate was 77.2% for the CAF+FT group and 74.6% for the CAF+FT+TAM group, and the 5-year disease-free survival rate was 56.7% for the CAF+FT group and 59.2% for the CAF+FT+TAM group. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. Analyses by factor revealed that the 5-year disease-free rate for lymph node-negative patients in the CAF+FT+TAM group was significantly higher than that for the corresponding patients in the CAF+FT group. No differences were noted in the incidence of adverse reactions between the two treatment groups, other than an increase in LDH (the frequency of which was higher in the CAF+FT+TAM group than in the CAF+FT group). Patients with estrogen receptor-negative [ ER(-)]breast cancer were treated with two types of regimens, ie, CAF+FT or CAF+FT+adriamycin(ADR), and the clinical benefit of the combined use of intermittent doses of ADR was evaluated. Of the 514 ER(-) patients registered in the trial, 478(93.0%) were eligible for evaluation. The 5-year survival rate was 64.9% for the CAF+FT group and 63.0% for the CAF+FT+ADR group, and the 5-year disease-free survival rate was 59.2% for both CAF+FT and CAF+FT+ADR groups. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. There were no significant differences between these groups in analyses by nodal or menopausal status. The incidences of adverse reactions including anorexia, nausea/vomiting and alopecia were higher in the CAF+FT+ADR group than in the CAF+FT group.